Joseph F. Merola

Raynaud's phenomenon: Pathogenesis and management

Raynauds phenomenon is a common clinical disorder for which patients frequently seek the expertise and care of dermatologists. It is manifested by recurrent vasospasm of the fingers and toes, often associated with exposure to cold temperature or emotional stress. The phenomenon is named after Maurice Raynaud, who, as a medical student, defined the first case in 1862 as episodic, symmetric, acral vasospasm characterized by pallor, cyanosis, suffusion, and a sense of fullness or tautness, which may be painful. Despite more than 140 years of research, the pathophysiology of Raynauds phenomenon continues to elude investigators. Accordingly, although many pharmacologic treatments have been reported, there is still no cure or gold standard therapy. Further, response to treatment varies and is difficult to predict. Recently, there has been renewed interest in finding the pathogenetic mechanisms of Raynauds phenomenon, an effort that has led to more potential targeted therapeutics. The purpose of this review is to discuss recent breakthroughs in the pathogenesis and treatment of Raynauds phenomenon.

Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis.

Background Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease‐modifying antirheumatic drugs (DMARDs). Methods In this 12‐month, double‐blind, active‐controlled and placebo‐controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5‐mg dose taken orally twice daily (107 patients), tofacitinib at a 10‐mg dose taken orally twice daily (104), adalimumab at a 40‐mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5‐mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10‐mg tofacitinib dose at 3 months (53). Placebo groups were pooled for analyses up to month 3. Primary end points were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) at month 3 and the change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ‐DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at month 3. Results ACR20 response rates at month 3 were 50% in the 5‐mg tofacitinib group and 61% in the 10‐mg tofacitinib group, as compared with 33% in the placebo group (P=0.01 for the comparison of the 5‐mg dose with placebo; P<0.001 for the comparison of the 10‐mg dose with placebo); the rate was 52% in the adalimumab group. The mean change in the HAQ‐DI score was ‐0.35 in the 5‐mg tofacitinib group and ‐0.40 in the 10‐mg tofacitinib group, as compared with ‐0.18 in the placebo group (P=0.006 for the comparison of the 5‐mg dose with placebo; P<0.001 for the comparison of the 10‐mg dose with placebo); the score change was ‐0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5‐mg tofacitinib group, 71% in the 10‐mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5‐mg tofacitinib dose, and 64% in the placebo group that switched to the 10‐mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial. Conclusions The efficacy of tofacitinib was superior to that of placebo at month 3 in patients with psoriatic arthritis who had previously had an inadequate response to conventional synthetic DMARDs. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Broaden ClinicalTrials.gov number, NCT01877668.)

Plakoglobin is O-glycosylated close to the N-terminal destruction box.

Plakoglobin provides a key linkage in protein chains that connect desmosomal and classical cadherins to the cytoskeleton. It is also present in a significant cytosolic pool that has the capacity to impact on canonical Wnt signaling by competing for interaction with partner proteins of β-catenin. The closely related protein, β-catenin, is rapidly targeted for proteasomal degradation by phosphorylation of a “destruction box” within the N-terminal domain. Inhibition of this process forms the basis of Wnt signaling. This destruction box is also found in the N-terminal domain of plakoglobin. We report that plakoglobin is modified by the addition of O-GlcNAc at a single site in close proximity to the destruction box. O-GlcNAc modification has been proposed to counteract phosphorylation, provide protection from proteasomal degradation, mediate signal transduction, silence transcription, and regulate multimolecular protein assembly. This finding has potential implications for understanding the roles of plakoglobin.

Cigarette smoking, alcohol consumption and risk of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease whose pathogenesis is thought to involve both genetic and environmental factors. It is possible that common environmental exposures, such as cigarette smoking and alcohol consumption, might modify risk of disease development in certain individuals. Here we aim to review the epidemiologic evidence related to the association of cigarette smoking, alcohol consumption and the risk of developing SLE. A growing body of evidence suggests that cigarette smoking confers a short-term increased risk of SLE in genetically susceptible individuals. On the other hand, alcohol consumption in moderate doses may have a protective effect against the development of SLE, although this is still debated. We also have reviewed proposed mechanistic explanations underlying the role of cigarette smoking and alcohol consumption in SLE pathogenesis.

Psoriasis, psoriatic arthritis and risk of gout in US men and women

Background and objective Individuals with psoriasis have increased blood levels of uric acid. However, there is no prospective data on the association between psoriasis and uric acid levels and subsequent development of gout. In this study, we examined the risk of gout among individuals with psoriasis and psoriatic arthritis (PsA) in two cohorts of men and women, the Health Professionals Follow-up Study (HPFS) (1986–2010) and Nurses’ Health Study (NHS) (1998–2010). Methods 27 751 men and 71 059 women were included in the analysis. Lifetime history of physician-diagnosed incident psoriasis and PsA was confirmed by validated supplementary questionnaires. Incident gout diagnoses were confirmed based on the American College of Rheumatology survey criteria. We used Cox proportional hazards models controlling for potential risk factors to calculate the HRs with 95% CIs of incident gout while simultaneously adjusting for several common risk factors. Results We documented 2217 incident cases of gout during follow-up. Psoriasis was associated with an increased risk of subsequent gout with a multivariate HR of 1.71 (95% CI 1.36 to 2.15) in the pooled analysis. Risk of gout was substantially augmented among those with psoriasis and concomitant PsA (pooled multivariate HR: 4.95, 95% CI 2.72 to 9.01) when compared to participants without psoriasis. Conclusions In this prospective study of US women and men, psoriasis and PsA were associated with an increased risk of gout.

Clinical manifestations and survival among adults with (SLE) according to age at diagnosis.

Objectives The objective of this paper is to determine the effect of clinical and laboratory manifestations, and medication prescribing, on survival according to patient age at diagnosis in a large academic systemic lupus erythematosus (SLE) cohort. Methods We identified SLE patients with a diagnosis at age ≥18, seen between 1970 through 2011, and with more than two visits to our lupus center. Data collection included SLE manifestations, serologies, other laboratory tests, medications, dates, and causes of death. We examined characteristics of those diagnosed before age 50 (adult onset) compared to those diagnosed at or after age 50 (late onset) using descriptive statistics. We used Kaplan-Meier curves with log rank tests to estimate five- and 10-year survival in age-stratified cohorts. Predictors of 10-year survival were assessed using Cox regression models, adjusted for calendar year, race/ethnicity, sex, lupus nephritis, and medication use. Results Of 928 SLE patients, the mean age at diagnosis was 35. Among the adult-onset group, there was significantly higher prevalence of malar rashes and lupus nephritis. Glucocorticoids, azathioprine, mycophenolate, and cyclophosphamide use were also more frequent in the adult-onset group compared to the late-onset group. Five-year survival rates were 99.5% and 94.9% and 10-year survival rates were 97.8% and 89.5%, among those diagnosed before and at or after age 50. In the entire cohort, increasing age at diagnosis, male sex, and black race were statistically significant predictors of reduced 10-year survival. Compared to those diagnosed before age 50, the late-onset group had a multivariable-adjusted hazard ratio for 10-year risk of death of 4.96 (95% CI 1.75–14.08). The most frequent cause of known death was a lupus manifestation, followed by cardiovascular disease and infection. Conclusions In our cohort, several demographic features, SLE manifestations, and medication prescribing differed between those with adult-onset and late-onset SLE. Ten-year survival rates were high for both groups, but relatively lower among late-onset patients. A lupus manifestation as the cause of death was more common among adult-onset compared with late-onset patients.

From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis

Background: An urgent need exists in the United States to establish treatment goals in psoriasis. Objective: We aim to establish defined treatment targets toward which clinicians and patients with psoriasis can strive to inform treatment decisions, reduce disease burden, and improve outcomes in practice. Methods: The National Psoriasis Foundation conducted a consensus‐building study among psoriasis experts using the Delphi method. The process consisted of: (1) literature review, (2) pre‐Delphi question selection and input from general dermatologists and patients, and (3) 4 Delphi rounds. Results: A total of 25 psoriasis experts participated in the Delphi process. The most preferred instrument was body surface area (BSA). The most preferred time for evaluating patient response after starting new therapies was at 3 months. The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or more from baseline. The target response at 3 months postinitiation was BSA 1% or less. During the maintenance period, evaluation every 6 months was most preferred. The target response at every 6 months maintenance evaluation is BSA 1% or less. Limitations: Although BSA is feasible in practice, it does not encompass health‐related quality of life, costs, and risks of side effects. Conclusion: With defined treatment targets, clinicians and patients can regularly evaluate treatment responses and perform benefit‐risk assessments of therapeutic options individualized to the patient.

Psoriasiform reactions to anti-tumor necrosis factor α therapy.

ObjectiveGiven increasing concern about the adverse effects of anti–tumor necrosis factor &agr; (anti–TNF-&agr;) medications, we sought to characterize psoriasiform eruptions in patients on these medications. MethodsIn a retrospective review of patients at the Brigham and Women’s Hospital combined dermatology-rheumatology clinic, we identified 13 patients (1 male and 12 female patients) who developed psoriasiform eruptions while on anti–TNF-&agr; medications. ResultsInciting medications were adalimumab, etanercept, and infliximab. Patients were on their inciting medication for a median time of 24 months and a mean time of 31.3 months before developing eruptions. Five of 7 patients experienced complete resolution of lesions with topical corticosteroids and discontinuation of anti–TNF-&agr; medications with the remaining 2 patients having partial improvement. One of the other 6 patients experienced complete resolution with topical corticosteroid treatment only, with the remaining 5 patients experiencing partial improvement. After changing anti–TNF-&agr; agents, 1 patient had partial improvement of psoriasiform lesions, and 7 patients had no improvement. ConclusionsAll of the main anti–TNF-&agr; medications currently used are capable of causing psoriasiform eruptions. Poor responders to topical agents, such as corticosteroids, may benefit from supplemental therapy aimed at the psoriasiform eruption or changing to a different class of immunomodulatory agents. Switching anti–TNF-&agr; medications had a low likelihood of improving psoriasiform skin reactions, further suggesting that these eruptions are a drug class effect.

Epidemiology and Treatment of Eosinophilic Fasciitis: An Analysis of 63 Patients From 3 Tertiary Care Centers

Author Contributions: Drs Hubiche and Valério had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hubiche, Valério, del Giudice. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Hubiche, Valério, del Giudice. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Hubiche, Valério. Administrative, technical, or material support: Hubiche, Mahe, Phan. Study supervision: Hubiche, Boralevi, Bodemer Skandalis, del Giudice.

The international dermatology outcome measures group: Formation of patient-centered outcome measures in dermatology

As quality standards are increasingly in demand throughout medicine, dermatology needs to establish outcome measures to quantify the effectiveness of treatments and providers. The International Dermatology Outcome Measures Group was established to address this need. Beginning with psoriasis, the group aims to create a tool considerate of patients and providers using the input of all relevant stakeholders in assessment of disease severity and response to treatment. Herein, we delineate the procedures through which consensus is being reached and the future directions of the project.